Roger Wrigglesworth

Novel series of 8H-quinazolino[4,3-b]quinazolin-8-ones via two Niementowski condensations

Efficient microwave-assisted multi-step synthesis of 8H-quinazolino[4,3-b]quinazolin-8-one was investigated. The synthesis involved two Niementowski condensations from anthranilic acids. Homogeneous or heterogeneous conditions were studied with the aim to develop convenient syntheses of the desired compounds.

Efficient synthesis of thiazoloquinazolinone derivatives

An original route to the rare 8H-thiazolo[5,4-f]quinazolin-9-one 1 and the novel 7H-thiazolo[4,5-h]quinazolin-6-one 2 is described. Access to the regioisomers was realized by fusion of a thiazole and a quinazoline ring via Appels salt chemistry. Thermal reactions were carried out using a focused microwave reactor, reducing the overall time of the multi-step synthesis.

Thiophene and bioisostere derivatives as new MMP12 inhibitors.

A new MMP12 inhibitor series has been identified containing a thiophene moiety. Different approaches have been considered to replace this potential toxicophore. α-Fluorothiophene derivatives were the most interesting compounds. Their synthesis is presented.

CoMFA and CoMSIA 3D-quantitative structure-activity relationship model on benzodiazepine derivatives, inhibitors of phosphodiesterase IV.

Recently, we reported structurally novel PDE4 inhibitors based on 1,4-benzodiazepine derivatives. The main interest in developing bezodiazepine-based PDE4 inhibitors is in their lack of adverse effects of emesis with respect to rolipram-like compounds. A large effort has thus been made toward the structural optimization of this series. In the absence of structural information on the inhibitor binding mode into the PDE4 active site, 2D-QSAR (H-QSAR) and two 3D-QSAR (CoMFA and CoMSIA) methods were applied to improve our understanding of the molecular mechanism controlling the PDE4 affinity of the benzodiazepine derivatives. As expected, the CoMSIA 3D contour maps have provided more information on the benzodiazepine interaction mode with the PDE4 active site whereas CoMFA has built the best tool for activity prediction. The 2D pharmacophoric model derived from CoMSIA fields is consistent with the crystal structure of the PDE4 active site reported recently. The combination of the 2D and 3D-QSAR models was used not only to predict new compounds from the structural optimization process, but also to screen a large library of bezodiazepine derivatives.